In recent years, microRNAs (miRs, miRNAs) have emerged as an important novel class of regulatory RNA, which has a profound impact on a wide array of biological processes. These small (typically 18-24 nucleotides long) non-coding RNA molecules can modulate protein expression patterns by promoting RNA degradation, inhibiting mRNA translation, and also affecting gene transcription. miRNAs play pivotal roles in diverse processes such as development and differentiation, control of cell proliferation, stress response and metabolism. Recent studies have revealed that miRNA expression in malignant cells can be affected by both genetic and epigenetic events associated with tumor growth. There are currently about 1,100 known human miRNAs. The expression of many of these has been found to be altered in numerous types of human cancer, and in some cases strong evidence has been put forward in support of the conjecture that such alterations may play a causative role in tumor progression via the regulation of tumor suppressors and oncogenes.
Mesothelioma is a tumor that occurs in the mesothelium that covers the surface of the pleura, peritoneum and pericardium that respectively envelop the organs of the chest cavity such as the lungs and heart, and abdominal organs such as the digestive tract and liver. In the case of diffuse pleural mesothelioma, chest pain is caused by invasion of the intercostal nerves on the side of the chest wall pleura, and respiratory and circulatory disorders may occur due to tumor growth and accumulation of pleural fluid in the pleura on the organ side (Takagi, Journal of Clinical and Experimental Medicine, (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999). Eventually, there is proliferation into the adjacent mediastinal organs, progressing to direct invasion of the heart or development in the abdominal cavity by means of the diaphragm, or there may be development outside the chest cavity as a result of additional lymphatic or circulatory metastasis.
In the U.S., diffuse pleural mesothelioma is reported to occur in 3,000 persons annually, with the number of cases increasing significantly through the 1980's. The disease is frequently observed in men in their sixties, with the incidence in men being roughly five times that in women. According to recent reports in the U.S. and Europe, the incidence of mesothelioma demonstrates a rapidly increasing trend, and, based on epidemiological statistics from the U.K. in 1995, the number of deaths from mesothelioma is predicted to continue to increase over the next 25 years. In the worst possible scenario, mesothelioma may be found to account for 1% of all deaths among men born in the 1940's.
Numerous different classification schemes for the clinical disease stages have been established for mesothelioma, and since the classification methods differ, comparison of the results of treatment for mesothelioma is difficult (Nakano, Environ Health Prev Med, 2008; 13:75-83).
In addition, malignant mesothelioma (MM) has a causative relationship with exposure to asbestos, and this has also been demonstrated in animal experiments (Tada, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 406-408, 1999). Asbestos that has been inhaled into the respiratory tract reaches a location directly beneath the pleura where a tumor eventually develops due to chronic irritation for typically 20 years, and this tumor spreads in a thin layer over the entire surface of the pleura. Consequently, although malignant mesothelioma is classified as an asbestos-related disease, not all malignant mesothelioma is caused by asbestos, and well-documented exposure is only observed in about half of all patients. Malignant pleural mesothelioma is resistant to treatment, associated with an extremely poor prognosis, and requires that countermeasures be taken immediately (Nakano, Environ Health Prev Med, 2008; 13: 75-83).
The prognosis for malignant mesothelioma is influenced by the stage of the disease. Surgery, when performed as part of a multimodality therapy with cytotoxic chemotherapy and radiation therapy, as well as adjuvant immunological treatments (e.g., interferon or interleukin) can be an effective treatment, but only in the rare event of diagnosis at an early stage.
In mesothelioma, the 9p21.3 deletions are often homozygous and linked with poor prognosis (Ivanov et al., Int J Cancer 2009; 124:589-599). Two tumor suppressor genes are localized in this area: CDKN2A (cyclin-dependent kinase inhibitor), which encodes the cell cycle inhibitory p16INK4A and p14ARF proteins, and the adjacent CDKN2B (p15INK4B) (Ruas and Peters, Biochim Biophys Acta 1998; 1378:F115-177). Combined deficiency of these products may have a synergistic effect in malignant transformation (Krimpenfort et al., Nature 2007; 448:943-946).
Much emphasis has been placed on the discovery and characterization of a unique tumor marker. However, no marker has yet been identified that has adequate sensitivity or specificity to be clinically useful, although a combination of multiple markers has been shown to increase prognostic accuracy. There is an unmet need for identification of specific and accurate markers associated with mesothelioma, especially those which could have prognostic significance in determining the type and extent of therapy necessary or reasonable for survival, and for compositions which could be employed in treating mesothelioma.